Factors influencing axial elongation in myopic children using overnight orthokeratology

Several factors influence axial length in children with myopia treated using overnight orthokeratology. To identify these factors, this retrospective study collected axial length and corneal aberration data on 78 eyes before and 1-year after orthokeratology. Patients were divided according to axial elongation (cut-off, 0.25 mm/year). Baseline characteristics included age, sex, spherical equivalent refraction, pupil diameter, axial length, and orthokeratology lens type. Corneal shape effects were compared through tangential difference maps. Group differences in higher-order aberrations of a 4 mm zone were compared at baseline and 1-year following therapy. Binary logistic regression analysis was conducted to identify the variables determined for axial elongation. Significant differences between both groups included the initial age of wearing orthokeratology lenses, type of orthokeratology lens, size of central flattening area, corneal total surface C12 (1-year), corneal total surface C8 (1-year), corneal total surface spherical aberration (SA) (1-year root mean square [RMS] values), change in total corneal surface C12, and change in front and total corneal surface SA (RMS values). The age when wearing an orthokeratology lens was the most important factor influencing axial length in children with orthokeratology-treated myopia, followed by lens type and change in the C12 of the total corneal surface.

OK lenses. There are two types of traditional OK lens design: vision shaping treatment (VST), as designed by Boston, and corneal refractive therapy (CRT) design, the design patent of Paragon. The parameters of the OK lens designed by VST comprises 4-5 arc segments, mainly including the base curve, reverse curve, alignment curve, and peripheral curve. The CRT lens design comprises three areas, including the central spherical zone, S-shaped return zone, and a non-curving landing zone (More information about the optical design can be found in the supplier's package insert. Paragon Z CRT, Package Insert, available online at: https:// www. acces sdata. fda. gov/ cdrh_ docs/ pdf5/ P0500 31c. pdf.). The schematic diagram and fluorescein pattern of the VST and CRT designs is presented in Fig. 1.
All patients were followed-up according to the standard process of the Ophthalmology Department of the First Affiliated Hospital of Zhejiang University. The OK lenses were fitted following the manufacturer recommendations. The patient was recommended to wear the OK lens for at least 8 consecutive hours every night after the lens was fitted. Patients were usually examined at 1 day, 1 week, and 1 month after wearing the OK, and follow-up was scheduled every 3 or 6 months subsequently. Visual acuity was measured at each visit, and a slit-lamp examination was performed to assess OK lens integrity and eye health. Axial length (AL) was measured every 6 months. Due to the heterogeneity of AL measurement intervals in clinical practice, we analysed only the 1-year values for the AL and number of days of wearing OK lenses. The change in the 1-year AL was calculated by subtracting the 1-year AL from the baseline value, multiplying by 365, and dividing by the number of days for which the OK lens was worn 26 . During the review period, lens wearing stopped for no more than 30 days on end for all patients.  www.nature.com/scientificreports/ AL and pupil diameter measurements. AL and pupil diameter were measured using optical ocular biometry (OA-2000, Tomey, Japan). The value of each parameter was calculated as the average of 10 consecutive measurements.
Refraction measurements. Cycloplegic autorefraction was measured using an auto-kerato-refractometer (ARK-1; Nidek, Japan) 35 min after the instillation of four drops of 0.5% tropicamide. Three successive measurements were performed, and their averages were used as representative values.
Corneal shape effect measurements. Tangential difference maps were created using 3-month topography values minus baseline topography values. The corneal flattening area (CFA) in the tangential difference maps was located within the central green ring, implying a power of ≤ 0 D (Fig. 2a). The colour of CFA was converted to red using ImageJ software (version 1.48; National Institutes of Health) (Fig. 2b), and the square value of CFA was calculated. A rectangular border was added outside the CFA (Fig. 2c). The eccentricity value was calculated as the distance between the centre of the rectangle and centre of the coordinate axis.
Higher-order aberration measurements. Higher-order aberrations of the front and total corneal surfaces for a 4 mm zone were measured simultaneously using the Sirius Scheimpflug-Placido topographer (CSO, Italy). Values were collected for C7 (vertical coma), C8 (horizontal coma), and C12 (spherical aberration, SA), the three Zernike polynomials, and the root mean square (RMS) values for coma aberration (coma), SA, and total higher-order aberration were calculated.

Figure 2.
Tangential difference maps were using 3-month topography minus baseline topography. The corneal flattening area (CFA) in the tangential difference maps was located within the central green ring, which means power ≤ 0D (a). The color of CFA was converted to red by ImageJ software, and the square value of CFA was also calculated by ImageJ software (b). A rectangular border was added outside of CFA (c), the eccentricity value was calculated by distance between the center of the rectangle and the center of the coordinate axis. (d) the square value of CFA was smaller in the effective group than the ineffective group. www.nature.com/scientificreports/ Data collection. Data were collected retrospectively from the clinical records of 78 eyes for statistical analysis, including the initial age at OK lens fitting, sex, baseline SER, baseline AL readings, pupil size, OK lens type, square value and eccentric value of the corneal flattening zone, and high-order aberrations of the front and total corneal surfaces, as detailed below.

Statistical analysis.
Depending on their characteristics, the data were described as frequencies, mean ± standard deviation, or median (minimum-maximum). Statistical analyses were performed to determine differences between all groups. The chi-square or modified chi-square test was used to evaluate categorical variables. Two independent sample t-tests or the Mann-Whitney U test was used to evaluate quantitative variables for analysing significant differences between groups. Spearman or Pearson correlation analysis was used to evaluate the relationship between the two variables. The relationships between risk factors and myopia control were evaluated using a bivariate logistic regression. The covariates in the bivariate logistic regression model included the initial age of OK lens fitting, OK lens type, square value of CFA, and change in SA (RMS value) on the total surface. A P value < 0.05 was considered statistically significant. All statistical tests were performed using SPSS Statistics for Windows version 19.0 (SPSS Inc., Chicago, IL, USA).

Results
Subjects and their characteristics. The study included 78 eyes that met the inclusion and exclusion criteria between 1 January 2021 and 31 December 2022. The eyes were divided into the effective (47 eyes) and ineffective groups (31 eyes). Table 1 presents the patients' demographic data. The average initial age at OK lens fitting was 10.33 ± 1.60 years, and 48.7% of patients were male. The average initial SER was 2.45 ± 1.03 D, the initial AL was 24.57 ± 0.53 mm, and the pupil diameter was 3.86 ± 0.52 mm. The two groups had similar values for sex distribution, SER, AL, and pupil diameter (P > 0.05). However, there were significant differences between both groups for the initial age at OK lens fitting (P < 0.001) and OK lens type (P = 0.003).
Changes in visual acuity. After wearing an OK lens for 1-year, the visual acuity of the naked eye increased considerably. However, there were no differences between both groups at baseline (p = 0.326) and 1-year postoperatively (p = 0.507).
Changes in high-order aberration measurements. After wearing the OK lens for 1-year, higher-order corneal aberration increased considerably. Higher-order aberrations of the front and total corneal surfaces in the 4 mm zone were compared between both groups at baseline and postoperatively ( Table 2). The effective group showed more negative values of C12 and C8 of the total corneal surface at 1-year postoperatively than at baseline (P = 0.023, C12; P = 0.031, C8). The P value of the SA (RMS value) was similar to that of C12. Changes in higher-order aberrations of the front and total corneal surfaces in the 4 mm zone at baseline and 1-year postoperatively were compared between both groups ( Table 3). The effective group showed a more negative change in C12 at the total corneal surface (P = 0.025). Moreover, the SA (RMS values) of the effective group showed a significant change at the front and total corneal surface (front P = 0.035; total P = 0.043).
Corneal shape effect differences. After wearing the OK lens for 3 months, the square value of CFA was significantly smaller in the effective group than in the ineffective group (11.07 ± 1.59 and 12.21 ± 1.91 mm 2 , respectively; P = 0.006; Fig. 2d). However, there were no differences in the eccentricity value of CFA between both groups (0.74 ± 0.42 and 0.63 ± 0.28 mm; P = 0.195).
Factors associated with AL changes. The associations between the risk factors and changes in AL were analysed using bivariate logistic regression ( Table 4). The covariates in the bivariate logistic regression model www.nature.com/scientificreports/   www.nature.com/scientificreports/ included the initial age at OK lens fitting, OK lens type, square value of CFA, total corneal surface of C8(1-year) and changes in the total corneal surface of C12. The results showed no significant change in AL between OK lens types (P = 0.079), square value of CFA (P = 0.56), total corneal surface of C8(1-year) (P = 0.546) and changes in the total corneal surface of C12 (P = 0.407). In contrast, the initial age at OK lens fitting significantly affected AL changes (P = 0.001). Age might be an independent factor affecting the ocular axis, but not the effect of OK lens. Therefore, the covariates in the second bivariate logistic regression model included only the OK lens type and changes in the total corneal surface of C12, as the initial age at OK lens fitting is not an effect of the OK lens, total corneal surface of C8 (1-year) (P > 0.5) and the square value of CFA was not significant (P > 0.5). Our results demonstrated a significant AL change between OK lens types (P = 0.031; Table 5).

Discussion
Our study found that the initial age of OK lens fitting, type of OK lens, SA, and central flattening area are factors affecting the myopia-controlling effect of OK lenses. In contrast to previous studies, we found that the type of OK lens and central flattening area might affect myopia control.
Our results indicate that the older a patient's age at baseline, the smaller the axial elongation 1-year after wearing the OK lens (P < 0.001, Table 1). This finding is consistent with the findings of Wang 15 and Santodomingo-Rubido 27 , who concluded that older myopic children at the initiation of OK lens wearing experienced slower AL growth than did younger children. However, even without OK lenses, the axial elongation rate decreases naturally with age 28 . Age may be the most important independent factor affecting axial growth. However, an OK lens can significantly delay axial progression 29 . Therefore, the effect of wearing OK lenses is predicted to be greater for older children with late-onset myopia.
Interestingly, OK lens type is the most important factor affecting myopia control if age as a factor is excluded. There are two main designs of OK lenses, namely VST and CRT. Brands of OK lenses include Menicon Z Night (Menicon Co., Ltd.), Alpha((Alpha Corp., Nagoya, Japan), Emerald (Euclid Systems Corporation, Herndon, VA), Euclid (Euclid Systems Corporation,USA), Hiline (Macro Vision, Taipei, Taiwan, China), and so on. We obtained CRT lenses from Paragon and VST lenses from Alpha, which displayed smaller axial elongation than the former lenses. Few studies have focused on this factor. Consistent with our results, Lu et al. found that VST lenses (brands: Euclid, Alpha, and Hiline) showed a better effect on myopia control but a weaker safety profile compared with the CRT lenses 30 . Moreover, Nakamura et al. found no differences among three types of VST lenses (brands: Menicon Z Night, Alpha, and Emerald) 31 .
The difference in the corneal shaping effect may be the main reason behind the difference in the myopiacontrolling effect between the two OK lens designs. Our results show that the size of central the flattening area is moderately related with the type of OK lens and is significantly larger in the Paragon CRT lenses than in the Alpha OK lenses (VST design). Similarly, Marcotte-Collard found that the Paragon CRT lenses generated a greater diameter of the central flattening zone on the cornea than the Dream lenses (VST design), leading to possible differences in myopia management efficacy 32 . The central flattening area is surrounded by an annular high convex zone that introduces myopic defocus to control myopia progression. Our results and Marcotte-Collard's findings demonstrate that the smaller the flattening area, the better the myopia control effect of the surrounding high convex zone.
Smaller CFA or the introduction of another myopic defocus of the CFA may be a step in the direction of improving OK lenses in the future. Paragon has launched a lens with a smaller optical zone (CRT 5.0 oz), which may have better myopia control. Multifocal OK, which has a dual-focus optics based on traditional OK lenses and, consequently, creates on-axis and peripheral myopic retinal defocus together, showed better myopia control than conventional OK lenses 33 . However, following the aforementioned changes, visual function declines at times. Nevertheless, ensuring both good distant vision and better myopia control effect is an aspect that needs further research.
In addition, high-order aberrations are another factor that affect myopia control. After OK treatment, the change in spherical aberrations (C12) becomes more negative, which may play a role in myopia progression. Our results showed that spherical aberrations were a relevant variable for axial elongation, consistent with the results of Lau 34 . The difference in the corneal shaping effect might be the main reason for the difference in spherical aberrations between both groups. Our results showed that the size of the central flattening area was moderately positively related with the change in spherical aberration (C12), and the size of the central flattening area was significantly smaller in the effective group than in the ineffective group. However, other studies reported different findings. For example, Hiraoka indicated that a coma aberration was a possible mechanism for slowing axial www.nature.com/scientificreports/ elongation in OK treatment 23 , but Santodomingo-Rubido showed that changes in corneal aberration were not significantly correlated with axial elongation 35 . Therefore, the influence of higher-order aberrations on ocular axis elongation requires further study. A limitation of this study was its retrospective nature. The control and study groups were not randomised. Further randomised studies on the relationship between corneal shape and myopia-controlling effects among different designs of OK lenses are warranted as may help improve future OK lens designs.
In summary, the initial age at OK lens fitting, type of OK lens, size of CFA, and spherical aberration affect the myopia-controlling effect of OK lenses. Notably, different types of OK lenses have different effects on myopia control.

Data availability
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.